Management of Cardiac Amyloidosis - Episode 2

Hypertrophic Cardiomyopathy Historical Prognosis

May 5, 2020


John L. Berk, MD: So, the patient comes into your office and they’ve been diagnosed with hypertrophic cardiomyopathy, they’re on standard medications, and they’re doing really poorly. Is that at all helpful in history, or is that just the way hypertrophic cardiomyopathies go?

Akshay S. Desai, MD, MPH: I think it’s an important phenotype to discuss. A lot of patients who come to cardiac attention are those with an established diagnosis of heart failure, often in the setting of preserved ejection fraction, who have increased wall thickness, as Dr Witteles outlined, in the absence of a typical stimulus for left ventricular hypertrophy. So, big thick walls in the absence of things that are associated with thick walls, like hypertension, I think should raise suspicion for a possible contributor.

In the case you described, where there’s a patient with a known or a presumed diagnosis of hypertrophic cardiomyopathy, who is responding poorly to therapies like β-blockers, I think the intolerance of standard therapy in the setting of hypertrophy or apparent hypertrophy should lead us to question the diagnosis, particularly if some of these auxiliary clues are present—orthostasis, peripheral neuropathy, biceps tendon rupture, bilateral carpal tunnel syndrome. So, I think the whole context of the patient in the historical features, in the setting of increased wall thickness, are things that should lead one to suspect that amyloidosis might be present. So those are some of the things that I think.

Another feature that I think is often useful, although not diagnostic and sometimes absent, is really to look at the ECG in the patient who has thick walls seen on echocardiography. If there is a discrepancy between the voltage on the ECG and the wall thickness on the echo, that might be a clue, although in many patients with defined or definite amyloid heart disease, that voltage discrepancy is not apparent.

So, I think there are a lot of clues, both from history—do you have the typical epidemiology, do you have the typical risk factors for development of hypertrophy? On physical exam, do you have some of these auxiliary signs or auxiliary diagnoses? On EKG, is there a discrepant voltage-to-mass ratio? Then, I think we can talk about other imaging features that may come up a little later in the program.

John L. Berk, MD: OK, thank you very much, Akshay.

Mazen Hanna, MD: But I just want to add something. As Dr Desai was speaking, I thought of a couple of other things. One of the pieces of the clinical history that is often seen in AL [amyloid light-chain amyloidosis], if you really ask for it, and maybe not often seen, but more specific to AL, is jaw claudication. Another physical exam finding that you can see in patients with AL is brittle nails. So, those 2 things I didn’t mention. And finally, in any patient who presents with HFpEF [heart failure with preserved ejection fraction] or thickened walls who has nephrotic range proteinuria, you’ve got to think about AL amyloidosis.

John L. Berk, MD: And the basis of the claudication, and then we’ll get to Ron?

Mazen Hanna, MD: I believe the basis of the jaw claudication is related to small-vessel ischemia. As we know, the amyloid deposits can deposit in the small vessels, and I believe it’s due to small-vessel ischemia when somebody is chewing, although we can see what Ron says.

John L. Berk, MD: Ron, you had a comment about macroglossia?

Ronald Witteles, MD: In terms of macroglossia, I think as cardiologists we aren’t used to looking at tongues very much. Anybody who treats amyloid does get used to looking at tongues. If you start looking at them, you’ll see there are people with true, honest-to-goodness, extreme macroglossia, sometimes to the point that they can’t even handle secretions, etc. That, as Maz was saying before, is really pathognomonic for AL amyloidosis. Transthyretin will not cause that. On the other hand, when you start looking for more subtle signs, and we often talk about scalloping of the tongue, which are the indentations from the upper teeth on the tongue, at least from my standpoint, I actually see that a fair bit in people with transthyretin amyloid. So when you read in the textbook, it does say AL amyloid, scalloping of the tongue is pathognomonic, and I think that’s only true for the more severe forms, not the less severe. I’m curious if others have found the same.

The other comment that I just wanted to make, in terms of wall thickness that was pointed out, indeed that if you see increased wall thickness without a clear cause, that’s 1 of the clear things you should be thinking about along with, for example, hypertrophic cardiomyopathy. But what I’d emphasize is that when you start getting into older populations, everybody has a history of hypertension. Just because somebody has a history of hypertension, that does not particularly explain massive wall thickening. For example, a very nice study just screening everybody with aortic stenosis found 16% of the individuals (just all-comers being screened) had concomitant transthyretin amyloidosis, 22% of them. So the main message I would say is if you see somebody with significant increased wall thickness, regardless of whether they have reasons why they should have increased wall thickness, amyloidosis—particularly transthyretin amyloidosis—actually should be 1 of the high considerations for the cause.

John L. Berk, MD: Thank you. Dr Desai, you had a comment?

Akshay S. Desai, MD, MPH: I was just going to build on what Ron said, and that is I think we’re starting to appreciate more and more that this very enigmatic problem of heart failure with preserved ejection fraction, where we’ve really had very little success in defining specific medical therapy, may be contaminated by a large proportion of particularly wild-type TTR [transthyretin] amyloid. So I think that deliberately looking, as has been suggested by the others, for amyloid in patients who have a little bit more wall thickening than you might expect for the degree of hypertension or the degree of aortic valve disease, suspecting and at least deliberately looking for those historical and physical exam clues in a patient who presents with HFpEF or low-gradient aortic stenosis, I think these are really important things. I think the data are suggesting to us that a large proportion of those patients may have undiagnosed amyloid. And it may be 1 of the reasons that some of our trials have really failed to hit because we’ve basically taken a population that has HFpEF that might respond to therapies, and then added in a substantial subset of people who have amyloid, that may need a very different approach.

John L. Berk, MD: Alright. Yes, Dr Hanna?

Transcript Edited for Clarity

Mazen Hanna, MD: I don’t want to belabor the point, but there’s 1 thing that Ron brought up in the beginning, that I just wanted to dovetail a little bit on—and that’s the epidemiology of the patient, the demographics of the patient. If a 53-year-old male walks into my office, is it possible that they have TTR cardiac amyloidosis? It is, but it’s probably going to be more likely it’s AL. So, in this era of increased imaging techniques and pyrophosphate scans, where people are not effectively ruling out AL, you have to think to yourself, does this 50-some-year-old patient actually have TTR? If you have an elderly patient, it’s going to be more likely ATTR than AL, not that it can’t be either. But in terms of demographic, if it’s an African American in their late 60s, you start to think of this hereditary form of ATTR. So, I think knowing the age and the sex of the patient, the demographic is important when you’re trying to think about these patients.